ABSTRACT Substantial evidence indicates that susceptibility to chronic obstructive pulmonary disease (COPD) is influenced by genetic factors, yet identification of causative variants remains challenging. Most genetic studies of complex diseases such as COPD have focused on the role of common genetic variation. However, several complex disease studies have demonstrated the importance of rare variants; these variants have typically been of relatively strong effect. This proposal will test the hypothesis that both rare and common variants in candidate genes from monogenic human syndromes, genome-wide association studies, and/or mouse emphysema models contribute to COPD susceptibility. We will test this hypothesis in 400 subjects with severe emphysema from the National Emphysema Treatment Trial and a set of 400 smoking controls with normal lung function from the Normative Aging Study, using second-generation sequencing technology. The specific aims are 1) variation discovery using a targeted, multiplexed approach on the Illumina Genome Analyzer; 2) rare variant analysis, using a collapsing method to combine variants and increase power, and 3) common variant analysis, including replication in the Boston Early-Onset COPD Study.